Ketamine: A Promising Rapid-Acting Antidepressant

Abstract

The monoaminergic deficiency hypothesis of depression has dominated the field of mood disorders research for several decades. This hypothesis has led to many advancements, including the theoretical underpinnings of the mechanism of action of all current oral antidepressants. However, the monoaminergic deficiency hypothesis does not fully explain the neurobiology of mood disorders, including the high rates of non-response and the delayed time between initiation of therapy and improvement in mood and related symptoms. Emerging evidence suggests a strong role for the glutamatergic system in the pathophysiology of mood disorders, which may provide more efficient therapeutic targets in the development of novel antidepressants. Ketamine, which acts directly on a glutamatergic receptor (N-methyl-d-aspartate receptor), has been shown to produce robust and rapid antidepressant effects after just a single dose. The effects of a single-dose have been replicated in several clinical trials of modest size. Less is known about multiple dosing protocols. While ketamine is approved by the Food and Drug Administration and similar agencies as an anesthetic, it is not approved in any country as an antidepressant. Concerns of the long-term effects on cognition and abuse from repeated ketamine exposure motivate the search for relapse prevention strategies that do not involve repeated administration of the drug. Given that a growing number of providers have begun offering ketamine off-label for the treatment of psychiatric disorders, future research is urgently needed to better understand long-term risks as well as evidence-based treatment regimens.